Progressive Optimization of Lanthanide Nanoparticle Scintillators for Enhanced Triple-Activated Radioluminescence Imaging.

Lanthanide nanoparticle (LnNP) scintillators exhibit huge potential in achieving radionuclide-activated luminescence (radioluminescence, RL). However, their structure-activity relationship remains largely unexplored. Herein, progressive optimization of LnNP scintillators is presented to unveil their structure-dependent RL property and enhance their RL output efficiency. Benefiting from the favorable host matrix and the luminescence-protective effect of core-shell engineering, NaGdF4 : 15 %Eu@NaLuF4 nanoparticle scintillators with tailored structures emerged as the top candidates. Living imaging experiments based on optimal LnNP scintillators validated the feasibility of laser-free continuous RL activated by clinical radiopharmaceuticals for tumor multiplex visualization. This research provides unprecedented insights into the rational design of LnNP scintillators, which would enable efficient energy conversion from Cerenkov luminescence, γ-radiation, and ß-electrons into visible photon signals, thus establishing a robust nanotechnology-aided approach for tumor-directed radio-phototheranostics.

Role of intracranial bone marrow mesenchymal stem cells in stroke recovery: A focus on post-stroke inflammation and mitochondrial transfer.

Stem cell therapy has become a hot research topic in the medical field in recent years, with enormous potential for treating a variety of diseases. In particular, bone marrow mesenchymal stem cells (BMSCs) have wide-ranging applications in the treatment of ischemic stroke, autoimmune diseases, tissue repair, and difficult-to-treat diseases. BMSCs can differentiate into multiple cell types and exhibit strong immunomodulatory properties. Although BMSCs can regulate the inflammatory response activated after stroke, the mechanism by which BMSCs regulate inflammation remains unclear and requires further study. Recently, stem cell therapy has emerged as a potentially effective approach for enhancing the recovery process following an ischemic stroke. For example, by regulating post-stroke inflammation and by transferring mitochondria to exert therapeutic effects. Therefore, this article reviews the therapeutic effects of intracranial BMSCs in regulating post-stroke inflammation and mitochondrial transfer in the treatment of stroke, providing a basis for further research.

Electroacupuncture attenuates nociceptive behaviors in a mouse model of cancer pain.

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.

Eugenol Possesses Colitis Protective Effects: Impacts on the TLR4/MyD88/NF-[Formula: see text]B Pathway, Intestinal Epithelial Barrier, and Macrophage Polarization.

Eugenol (EU) has been shown to ameliorate experimental colitis due to its anti-oxidant and anti-inflammatory bioactivities. In this study, DSS-induced acute colitis was established and applied to clarify the regulation efficacy of EU on intestinal barrier impairment and macrophage polarization imbalance along with the inflammatory response. Besides, the adjusting effect of EU on macrophages was further investigated in vitro. The results confirmed that EU intervention alleviated DSS-induced colitis through methods such as restraining weight loss and colonic shortening and decreasing DAI scores. Microscopic observation manifested that EU maintained the intestinal barrier integrity in line with the mucus barrier and tight junction protection. Furthermore, EU intervention significantly suppressed the activation of TLR4/MyD88/NF-[Formula: see text]B signaling pathways and pro-inflammatory cytokines gene expressions, while enhancing the expressions of anti-inflammatory cytokines. Simultaneously, WB and FCM analyses of the CD86 and CD206 showed that EU could regulate the DSS-induced macrophage polarization imbalance. Overall, our data further elucidated the mechanism of EU's defensive effect on experimental colitis, which is relevant to the protective efficacy of intestinal barriers, inhibition of oxidative stress and excessive inflammatory response, and reprogramming of macrophage polarization. Hence, this study may facilitate a better understanding of the protective action of the EU against UC.

NIR-II imaging-guided precise photodynamic therapy for augmenting tumor-starvation therapy by glucose metabolism reprogramming interference.

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy-D-glucose (2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy (PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle (LnNP) cores was constructed and combined with mesoporous silicon shells loaded with 2DG and photosensitizer chlorin e6 (Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared (NIR-II, 1000-1700 nm) window from the LnNPs was used to monitor the accumulation of nanomaterials in tumors. Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system.

A continuously efficient O2-supplying strategy for long-term modulation of hypoxic tumor microenvironment to enhance long-acting radionuclides internal therapy.

Radionuclides internal radiotherapy (RIT) is a clinically powerful method for cancer treatment, but still poses unsatisfactory therapeutic outcomes due to the hypoxic characteristic of tumor microenvironment (TME). Catalase (CAT) or CAT-like nanomaterials can be used to enzymatically decompose TME endogenous H2O2 to boost TME oxygenation and thus alleviate the hypoxic level within tumors, but their effectiveness is still hindered by the short-lasting of hypoxia relief owing to their poor stability or degradability, thereby failing to match the long therapeutic duration of RIT. Herein, we proposed an innovative strategy of using facet-dependent CAT-like Pd-based two-dimensional (2D) nanoplatforms to continuously enhance RIT. Specifically, rationally designed 2D Pd@Au nanosheets (NSs) enable consistent enzymatic conversion of endogenous H2O2 into O2 to overcome hypoxia-induced RIT resistance. Furthermore, partially coated Au layer afford NIR-II responsiveness and moderate photothermal treatment that augmenting their enzymatic functionality. This approach with dual-effect paves the way for reshaping TME and consequently facilitating the brachytherapy ablation of cancer. Our work offers a significant advancement in the integration of catalytic nanomedicine and nuclear medicine, with the overarching goal of amplifying the clinical benefits of RIT-treated patients.

Mitochondrial Transplantation and Immune Response of Human Bone Marrow Mesenchymal Stem Cells for the Therapeutic of Ischemic Stroke.

Ischemic stroke is the leading cause of death and disability worldwide, with increasing incidence and mortality, imposing a significant social and economic burden on patients and their families. However, cerebral vascular occlusion leads to acute loss of neurons and destruction of synaptic structures. The limited treatment options cannot adequately address intra-neuronal mitochondrial dysfunction due to stroke. Therefore, stem cell-derived mitochondria transplantation plays an important role in neuronal protection and recovery after stroke, when combined with the intracranial and extracranial immunoregulatory effects of stem cell therapy, revealing the mechanism of transferred mitochondria in stem cells in protecting neurological function among chronic-phase ischemic stroke by affecting the endogenous apoptotic pathway of neuronal cells. This research elaborated on the mitochondrial dysfunction in neurons after ischemic stroke, followed by human bone marrow mesenchymal stem cells (hBMSC) rescued damaged neurons by mitochondrial transfer through tunneling nanotubes (TNTs), and the immunomodulatory effect of the preferential transfer of stem cells to the spleen when transplanted into the body.which created an immune environment for nerve repair, as well as improved neurological recovery after the chronic phase of stroke. This review is expected to provide a novel idea for applying intracranial stem cell transplantation in chronic-phase ischemic stroke treatment.

An Extended NIR-II Superior Imaging Window from 1500 to 1900†nm for High-Resolution In Vivo Multiplexed Imaging Based on Lanthanide Nanocrystals.

High-resolution in vivo optical multiplexing in second near-infrared window (NIR-II, 1000-1700 nm) is vital to biomedical research. Presently, limited by bio-tissue scattering, only luminescent probes located at NIR-IIb (1500-1700 nm) window can provide high-resolution in vivo multiplexed imaging. However, the number of available luminescent probes in this narrow NIR-IIb region is limited, which hampers the available multiplexed channels of in vivo imaging. To overcome the above challenges, through theoretical simulation we expanded the conventional NIR-IIb window to NIR-II long-wavelength (NIR-II-L, 1500-1900 nm) window on the basis of photon-scattering and water-absorption. We developed a series of novel lanthanide luminescent nanoprobes with emission wavelengths from 1852 nm to 2842 nm. NIR-II-L nanoprobes enabled high-resolution in vivo dynamic multiplexed imaging on blood vessels and intestines, and provided multi-channels imaging on lymph tubes, tumors and intestines. The proposed NIR-II-L probes without mutual interference are powerful tools for high-contrast in vivo multiplexed detection, which holds promise for revealing physiological process in living body.

A self-charging salt water battery for antitumor therapy.

Implantable devices on the tumor tissue as a local treatment are able to work in situ, which minimizes systemic toxicities and adverse effects. Here, we demonstrated an implantable self-charging battery that can regulate tumor microenvironment persistently by the well-designed electrode redox reaction. The battery consists of biocompatible polyimide electrode and zinc electrode, which can consume oxygen sustainably during battery discharge/self-charge cycle, thus modulating hypoxia level in tumor microenvironment. The oxygen reduction in battery leads to the formation of reactive oxygen species, showing 100% prevention on tumor formation. Sustainable consumption of oxygen causes adequate intratumoral hypoxic conditions over the course of 14 days, which is helpful for the hypoxia-activated prodrugs (HAPs) to kill tumor cells. The synergistic effect of the battery/HAPs can deliver more than 90% antitumor rate. Using redox reactions in electrochemical battery provides a potential approach for the tumor inhibition and regulation of tumor microenvironment.

[Myrislignan Induces Apoptosis in Gastric Cancer Cell Line Through PI3K/AKT Signaling Pathway].

Objective: To investigate the effect of myrislignan (MYR) on the apoptosis of gastric cancer cell line and its relationship with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Methods: The gastric cells (SGC-7901) were treated with MYR at different concentrations, i.e., 0, 25, 50, 100, and 200 µmol/L, for 48 h and 72 h and the effect of MYR on the proliferation of SGC-7901 cells was measured by CCK-8 assay. Then, SGC-7901 cells were treated with different concentrations of MYR at 50, 100, and 200 µmol/L for 48 h. Meanwhile, a normal control group and a dimethyl sulfoxide (DMSO) solvent control group (0.1% DMSO) were established. Flow cytometry was used to determine the apoptosis rate of SGC-7901 cells. The protein expression levels of PI3K, AKT, Bcl-2-associated X protein (BAX), cysteine-dependent aspartate-specifc protease-3 (Caspase-3), and Caspase-9 were determined by Western blot. Then, PI3K activator (20 µmol/mL) was used to treat SGC-7901 cells for 48 h in 4 groups, the control group, 0.1% DMSO group, MYR group, and MYR+PI3K activator group, and the effect on MYR's induction of apoptosis and regulation of the protein expression levels of PI3K, AKT, BAX, Caspase-3, and Caspase-9 in SGC-7901 cells. Results: Compared with the control group, MYR at 50, 100 and 200 µmol/L inhibited the proliferation of gastric cancer cells, increased the apoptosis rate, down-regulated the protein expression levels of PI3K and AKT, and up-regulated the protein expression levels of BAX, Caspase-3, and Caspase-9 in a dose-dependent manner ( P<0.05). However, PI3K activator attenuated MYR-induced apoptosis in gastric cancer cells and MYR's regulation of PI3K, AKT, BAX, Caspase-3, and Caspase-9 protein expression ( P<0.05). Conclusion: MYR induces the expression of BAX, Caspase-3, and Caspase-9 proteins by inhibiting the PI3K/AKT signaling pathway, thereby promoting the apoptosis of gastric cancer cells.

Real-World clinical features and survival outcomes associated with primary gastrointestinal natural killer/T-cell lymphoma from 1999 to 2020.

BACKGROUND: Primary gastrointestinal natural killer (NK)/T-cell lymphoma (PGINKTL) is a rare T-/NK-cell lymphoma subtype, and the clinical features and survival outcomes remain largely unknown. METHODS: To summarize the clinical features and survival outcomes of PGINKTL, PGINKTL cases diagnosed at our hospital from May 1999 to December 2020 were reviewed; and the clinical data, information on treatment strategies, and survival were collected. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional hazards regression. We constructed a nomogram to visualize the survival prediction of PGINKTL. The discriminative ability and calibration of the nomogram for prediction were tested using the concordance index (C-index) and calibration plots. RESULTS: The cohort included 81 cases, the median age was 36 years (range, 7-80 years), and the male-to-female ratio was 1.7:1. The most common clinical symptom at the time of diagnosis was abdominal pain (71.6%). The most common lesion site was the colon (59.3%). During a median follow-up period of 37.7 months, the median overall survival (OS) time of 81 patients was 4.0 months (95% confidence interval [CI], 3.1-4.9 months), and the 2-year OS rate was 30.7% (95% CI, 20.3%-40.1%). The multivariate analyses indicated that patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥2, serum lactic dehydrogenase (LDH) level ≥ the upper limit normal (ULN), and perforation had worse OS. We used these data to establish a nomogram to predict survival for PGINKTL. The nomogram displayed good accuracy, with a C-index of 0.726. CONCLUSION: The clinical features and poor outcomes of PGINKTL, which is a rare and fatal lymphoma type, are presented. The proposed nomogram provides an individualized estimate of survival for these patients. In the future, the study focused on exploring a better treatment strategy to improve survival is required in PGINKTL.

[Therapeutic Effect of Artesunate on Influenza A Viral Pneumonia].

Objective: To investigate the therapeutic effect of artesunate (ART) on influenza A viral pneumonia. Methods: A total of 36 mice were evenly and randomly assigned to six groups, a normal control group (C group), a solvent control group (M group, 10% DMSO), a positive drug group (P group, oseltamivir, 1.25 mg/kg/day), ART high-dose group (ART-G group, 120 mg/kg/day), ART medium-dose group (ART-Z group, 60 mg/kg/day), and ART low-dose group (ART-D group, 30 mg/kg/day). Except for group C, which did not receive any influenza A virus intervention or intraperitoneal injection, mice in the five other groups were infected with influenza A virus through intranasal drip. Then, after 12 hours, mice in the five other groups received intraperitoneal injection of the assigned drugs and dosage once a day. The signs, body weight, and survival of the mice were observed over the course of treatment. After 7 days of treatment, the lung tissue of the mice was collected and weighed, and the lung index was calculated accordingly. HE staining was performed to observe the pathological changes in the lung tissue. The mRNA and protein expression levels of Toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB [p65]), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and IL-1ß were examined with RT-qPCR and Western blot, respectively. Results: Compared with those in C group, mice in the M group had worse physical signs and lower body mass and survival, increased lung index, severe pathological changes in lung tissue, and increased levels of TLR4, NF-κB (p65), TNF-α, IL-6 and IL-1ß mRNA and protein expression in their lung tissue ( P<0.05). Compared with those in M group, the mice in the ART groups had better physical signs, higher body mass and survival rate, decreased lung index, improvement of pathological changes in the lung tissue, and decreased levels of level of TLR4, NF-κB (p65), TNF-α, IL-6 and IL-1ß mRNA and protein expression in the lung tissue ( P<0.05). Furthermore, the most prominent changes in these indexes were observed in the ART-G group. Conclusion: ART has therapeutic effects on influenza A viral pneumonia, and the mechanisms are related to the inhibition of TLR4/p65 signaling pathway activation and anti-inflammation.

[Effect and mechanism of acupoint injection on influenza A virus induced pneumonia in mice].

OBJECTIVE: To investigate the effect and mechanism of acupoint injection with 0.1% vitamin C+vitamin B complex solution (VC+VBCo) at "Tiantu" (CV 22), "Quchi" (LI 11) and "Zusanli" (ST 36) in mouse model of pneumonia induced by influenza A virus (A/PR/8/34 [H1N1], PR8). METHODS: Sixty male ICR mice were randomized into 6 groups, i.e. control group, model group, acupoint injection group, intraperitoneal injection group, non-target point group and ribavirin group, 10 mice in each one. Except the control group, the pneumonia models were induced by slow nasal dripping PR8 virus in the other groups. On the 2nd day of experiment, VC+VBCo solution, 40 µL was injected at "Tiantu" (CV 22), "Quchi" (LI 11, left) and "Zusanli" (ST 36, left) in the acupoint injection group; VC+VBCo solution, 120 µL was injected intraperitoneally in the intraperitoneal injection group; VC+VBCo solution, 40 µL was injected at non-target acupoints (0.5 cm away from "Tiantu" [CV 22] to the left side, "Quchi" [LI 11, left] and "Zusanli" [ST 36, left]) in the non-target point group; and ribavirin solution, 120 µL was injected intraperitoneally in the ribavirin group. The intervention was delivered once daily, for consecutive 7 days. Three parallel experiments were undertaken. The mean death rate and survival time were assessed in each group, the body mass and lung index were compared among groups. Using HE staining, the morphology of lung tissue was observed; and with real-time fluorescence quantitative PCR, viral load in lung tissue was detected. The concentrations of inflammatory factors (tumor necrosis factor α [TNF-α], interleukin [IL]-1ß, IL-10) were detected in lung tissue of each group using ELISA; and those of oxidative stress markers (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], malondialdehyde [MDA]) were detected with chemiluminescence method. RESULTS: Compared with the control group, the body mass was decreased and lung index was increased in the model group (P<0.01). In comparison with the model group, body mass was increased in the acupoint injection group (P<0.05), lung index was reduced in the acupoint injection group the and ribavirin group (P<0.05); the mean death rate was decreased and the mean survival time prolonged in the mice of the acupoint injection group (P<0.01, P<0.05); and the mean death rate was reduced in the mice of the ribavirin group (P<0.05). In the model group, the alveolar structure was not integral, the alveolar septum was thickened, inflammatory cells were infiltrated and red blood cells exudated seriously (P<0.01). Compared with the model group, in the acupoint injection group and the ribavirin group, the alveolar structure was integral, the thickened alveolar septum was alleviated; and the infiltration of inflammatory cells and the exudation of red blood cells were reduced remarkably. The viral load was reduced in the mice of the ribavirin group when compared with the model group (P<0.01). Compared with the control group, the concentrations of TNF-α, IL-1ß and MDA in lung tissue were increased and those of IL-10, SOD and GSH-Px were reduced in the model group (P<0.01). In the acupoint injection group and the ribavirin group, the concentrations of TNF-α, IL-1ß and MDA were reduced in lung tissue and those of IL-10, SOD and GSH-Px were increased (P<0.05, P<0.01) when compared with the model group. CONCLUSION: Acupoint injection with VC+VBCo solution may alleviate inflammatory responses and oxidative stress in lung tissue of the PR8-induced pneumonia mice, improve survival rate and prolong the survival time in the case of no effect of the viral load.

A LRET Nanoplatform Consisting of Lanthanide and Amorphous Manganese Oxide for NIR-II Luminescence Lifetime Imaging of Tumor Redox Status.

Designing luminescence lifetime sensors in the second near-infrared (NIR-II) window is a great challenge due to the difficult structural construction. Here, we report a tumor redox responsive and easily synthesized material, amorphous manganese oxide (MnOx ) with indirect band gap of 1.02 eV, as an energy acceptor to build a luminescence resonance energy transfer (LRET) toolbox for universally regulating NIR-I to NIR-II luminescence lifetimes of lanthanide nanoparticles, in which energy transfer is based on matched energy gap instead of conventional overlapped spectra. We further utilize ytterbium (Yb3+ )-doped YbNP@MnOx as an NIR-II luminescence lifetime sensor to realize in vitro quantitative redox visualization with relative errors under 5 % in samples covered with mouse skin. Furthermore, HepG2 cells and tumors with high redox state have been accurately distinguished by NIR-II luminescence lifetime imaging. The quantified intracellular and intratumor glutathione (GSH) levels are highly consistent with the commercial kit results, illustrating the reliable redox visualization ability in biological tissue.

Effectiveness and Safety of PD-1 Inhibitor Monotherapy for Elderly Patients with Advanced Non-Small Cell Lung Cancer: A Real-World Exploratory Study.

Background: Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective: This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods: Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results: The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65-82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%-32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%-74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4-4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3-14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion: PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC.

Ligand Engineering of Titanium-Oxo Nanoclusters for Cerenkov Radiation-Reinforced Photo/Chemodynamic Tumor Therapy.

The therapeutic effect of general photodynamic therapy (PDT) is gravely limited by the poor penetration depth of exogenous light radiation. In recent years, Cerenkov radiation (CR) has been exploringly applied to overcome this critical defect. However, the currently reported type I photosensitizers for CR-induced PDT (CRIT) are only TiO2 nanoparticle-based agents with numerous fatally intrinsic drawbacks. Herein, we developed NH2-Ti32O16 nanocluster (NTOC)-derived ultrasmall nanophotosensitizers (NPSs, denoted as TDPs) via innovate ligand engineering. The introduced dopamine (DA) ligands not only facilitate the water solubility and photocatalytic properties of NPSs but also involve the tumor-targeting behavior through the binding affinity with DA receptors on cancer cells. Under CR irradiation, TDPs enable efficient hydroxyl radical (·OH) generation benefiting from the enhanced separation of hole (h+)-electron (e-) pairs, where the h+ will react with H2O to execute type I PDT and the transferred e- can realize the augmentation of Ti3+ to substantially promote the therapeutic index of chemodynamic therapy. This study provides an easy but feasible strategy for constructing versatile NPSs with an ultrasmall framework structure, propounding a refreshing paradigm for implementing efficient CR-induced combined therapy (CRICT) and spurring the development of CR and titanium-familial nanoplatforms in the fields of photocatalysis and nanocatalytic medicine.

High-Fidelity NIR-II Multiplexed Lifetime Bioimaging with Bright Double Interfaced Lanthanide Nanoparticles.

Fluorescence lifetime imaging provides more possibility of in vivo multiplexing in second near infrared (NIR-II) window. However, it still faces the obstacle that fluorescent probes with differentiable lifetime often exhibit quite different fluorescence intensity, especially the short lifetime usually accompanies with a weak fluorescence intensity, resulting in the difficulty for simultaneously decoding multiplexed lifetime information due to the interference of background noise. To facilitate high-fidelity lifetime multiplexed imaging, we developed a series of Er3+ doped double interface fluorescent nanoprobes (Er-DINPs): α-NaYF4 @NaErF4 : Ce@NaYbF4 @NaErF4 : Ce@NaYF4 with strong fluorescence intensity and easily distinguishable fluorescence lifetime. Both in vitro and in vivo experimental results confirmed the advantage of these probes with comparable fluorescence intensity for high-fidelity multiplexed lifetime bioimaging.

NIR-II cell endocytosis-activated fluorescent probes for in vivo high-contrast bioimaging diagnostics.

Fluorescence probes have great potential to empower bioimaging, precision clinical diagnostics and surgery. However, current probes are limited to in vivo high-contrast diagnostics, due to the substantial background interference from tissue scattering and nonspecific activation in blood and normal tissues. Here, we developed a kind of cell endocytosis-activated fluorescence (CEAF) probe, which consists of a hydrophilic polymer unit and an acid pH-sensitive small-molecule fluorescent moiety that operates in the "tissue-transparent" second near-infrared (NIR-II) window. The CEAF probe stably presents in the form of quenched nanoaggregates in water and blood, and can be selectively activated and retained in lysosomes through cell endocytosis, driven by a synergetic mechanism of disaggregation and protonation. In vivo imaging of tumor and inflammation with a passive-targeting and affinity-tagged CEAF probe, respectively, yields highly specific signals with target-to-background ratios over 15 and prolonged observation time up to 35 hours, enabling positive implications for surgical, diagnostic and fundamental biomedical studies.

Zc3h12d, a Novel of Hypomethylated and Immune-Related for Prognostic Marker of Lung Adenocarcinoma.

BACKGROUND: Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD. METHODS: TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples' data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan-Meier plotter and our samples' data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort. RESULTS: Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression. CONCLUSION: zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.

Versatile fluorinated Pd@Au nanoplates doped with yttrium for tumor theranostics.

As one of the emerging modalities of magnetic resonance imaging (MRI), 19F MRI is highly conducive for the specific detection and imaging of deep-seated tumors, with negligible background. However, most 19F MRI probe designs are constructed with organic CF3, which contains rich fluorine atoms, and few of the fluorine-containing groups are equipped with therapeutic function. Herein, we designed a versatile 19F MRI-based theranostic nanoplatform, FY-Pd@Au nano-metallacages (FY-Pd@Au NCs), which not only serve as a 19F MRI/CT/PAI contrast agent, but also produce reactive oxygen species (ROS) by type I photodynamic therapy (PDT) pathway, as well as heat for photothermal therapy (PTT), under the single NIR laser irradiation. Overall, this work successfully built a theranostics nanoplatform based on 19F MRI.